Not Applicable.
This invention relates to a method for treating or preventing hyperparathyroidism utilizing an active vitamin D compound.
Hyperparathyroidism is a generalized disorder resulting from excessive secretion of parathyroid hormone (PTH) by one or more parathyroid glands. It is thus characterized by elevated blood levels of parathyroid hormone. Typically, one or more parathyroid glands reveal a marked enlargement. In the case of primary hyperparathyroidism, the glandular enlargement is usually due to a neoplasm or tumor. In the case of secondary hyperparathyroidism, the parathyroid gland hyperplasia typically occurs because of resistance to the metabolic actions of the hormone. Secondary hyperparathyroidism occurs in patients with, e.g., renal failure, osteomalacia, and intestinal malabsorption syndrome. In both primary and secondary hyperparathyroidism, bone abnormalities, e.g., the loss of bone mass or decreased mineral content, are common and renal damage is possible. Hyperparathyroidism is thus also characterized by abnormal calcium, phosphorus and bone metabolism.
It has long been known that vitamin D plays a critical role regulating calcium metabolism. The discovery of the active forms of vitamin D in the 1970""s [M. F. Holick et al., Proc. Natl. Acad. Sci. USA 68, 803-804 (1971); G. Jones et al., Biochemistry 14, 1250-1256 (1975)] and active vitamin D analogues [M. F. Holick et al., Science 180, 190, 191 (1973); H. Y. Lam et al., Science 186, 1038-1040 (1974)], caused much excitement and speculation about the usefulness of these compounds in the treatment of bone depletive disorders.
Animal and early clinical studies examining the effects of these active vitamin D compounds suggested that such agents would be useful in restoring calcium balance. However, the best indicator of the efficacy of vitamin D compounds to prevent or treat depletive bone disorders is bone itself (or, in the case of renal osteodystrophy, serum levels of parathyroid hormone (PTH)) rather than calcium absorption or calcium balance. Certain clinical studies with 1xcex1,25-(OH)2 vitamin D3, and 1xcex1-OH vitamin D3 indicate that the ability of these agents to restore lost bone mass or bone mineral content is dose-related. [See, S. M. Ott, C. H. Chesnut, Annals of Int. Med 1989; 110:267-274; J. C. Gallagher et al., Annals of Int. Med. 1990; 113:649-655; J. Aloia et al., Amer. J Med 84:401-08 (1988)] M. Shiraki et al., Endocrinol. Japan 32, 305-315 (1985)].
These clinical studies also indicate that at the dosage ranges required for these agents to be truly effective, toxicity in the form of hypercalcemia and hypercalciuria becomes a major problem. Attempts to increase the amount of 1xcex1,25-(OH)2 vitamin D3 above 0.5 xcexcg/day have frequently resulted in toxicity. At dosage levels below 0.5 xcexcg/day, clinically significant effects on bone are rarely observed. [See G. F. Jensen et al., Clin. Endocrinol. 16, 515-524 (1982); C. Christiansen et al., Eur. J Clin. Invest. 11, 305-309 (1981)]. Doses of 2 xcexcg/day of 1xcex1-OH vitamin D3 were found to have efficacy in increasing bone mass in patients exhibiting senile osteoporosis [O. H. Sorensen et al., Clin. Endocrinol. 7, 169S-175S (1977)]. Data from clinical studies in Japan, a population that has low calcium intake, indicate that efficacy is found with 1xcex1-OH vitamin D3 when administered at 1 xcexcg/day [M. Shiraki et al., Endocrinol. Japan. 32:305-315 (1985); H. Orimo et al., Bone and Mineral 3, 47-52 (1987)]. However, at 2 xcexcg/day, toxicity with 1xcex1-OH vitamin D3 occurs in approximately 67 percent of the patients, and at 1 xcexcg/day this percentage is approximately 20 percent.
Thus, the prior art teaches that due to their toxicity, 1-hydroxylated vitamin D compounds can only be administered at dosages that are, at best, modestly beneficial in preventing or treating loss of bone or bone mineral content. Indeed, Aloia recommends that alternative routes of administration be sought which might avoid the toxicity problems and allow higher dosage levels to be achieved. [J. Aloia et al., Amer. J Med 84:401-408 (1988)]. Despite reported toxicities of 1xcex1-OH vitamin D3 and 1xcex1,25-(OH)2 vitamin D3, these two compounds remain the drugs of choice for many bone depletive disease treatments.
As to secondary hyperparathyroidism and its occurrence in renal failure, at present, in the United States, end stage renal disease afflicts approximately 200,000 individuals. In this disease, there is a progressive loss of cells of the proximal nephrons, the primary site for the synthesis of the vitamin D hormones (collectively xe2x80x9c1xcex1,25-(OH)2Dxe2x80x9d) from 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2. In addition, the loss of functioning nephrons leads to retention of excess phosphorus which reduces the activity of the renal 25-hydroxyvitamin D-1xcex1-hydroxylase, the enzyme which catalyzes the reaction to produce the D hormones. These two events account for the low serum levels of 1xcex1,25-(OH)2D commonly found in patients with mild to moderate end stage renal disease.
Reduced serum levels of 1xcex1,25-(OH)2D cause increased, and ultimately excessive, secretion of PTH by direct and indirect mechanisms. The resulting hyperparathyroidism leads to markedly increased bone turnover and its sequela of renal osteodystrophy, which may include a variety of other diseases, such as, osteitis fibrosa cystica, osteomalacia, osteoporosis, extraskeletal calcification and related disorders, e.g., bone pain, periarticular inflammation and Mockerberg""s sclerosis. Reduced serum levels of 1xcex1,25-(OH)2D also can cause muscle weakness and growth retardation with skeletal deformities (most often seen in pediatric patients).
Previous clinical studies of hormonally active vitamin D drugs in end stage renal disease patients have focused on compounds derived from vitamin D3. 1xcex1,25-(OH)2D3 and 1xcex1-OH-D3 are the major approved forms of 1xcex1-hydroxylated vitamin D for treatment or prevention, although these drugs are not currently approved in all major pharmaceutical markets. Use of 1xcex1,25-(OH)2D3 and 1xcex1-OH-vitamin D3 as replacement therapy seeks to treat or prevent renal osteodystrophy by treating or preventing hyperparathyroidism in end stage renal disease patients. As noted above, 1xcex1,25-(OH)2D3 often causes toxic side effects (hypercalcemia and hyperphosphatemia) at dosages above 0.5 xcexcg, especially when concomitantly administered calcium phosphate binders are used to control serum phosphorus. The minimum effective dose for preventing hyperparathyroidism is in the range of 0.25 to 0.50 xcexcg/day; most patients respond to oral treatment doses of 0.5 to 1.0 xcexcg/day or intravenous doses between 0.5 and 3.0 xcexcg three times per week. As described above, the other commonly used vitamin D drug is 1xcex1-OH-D3 which often causes toxic effects at dosages over 1.0 xcexcg/day, especially when used with calcium phosphate binders. The minimum effective dosage for preventing hyperparathyroidism is in the range of 0.25 to 1.0 xcexcg/day, and most patients require treatment dosages of 1.0 xcexcg/day or more. When either drug, 1xcex1,25-(OH)2D3 or 1xcex1-OH-D3, is administered in higher dosages, both efficacy and toxicity are found to increase. Thus, the hormonally active vitamin D3 compounds are limited in their therapeutic usefulness due to their inherent toxicities.
To reduce the incidence of toxic side effects with 1xcex1,25-(OH)2D3 or 1xcex1-OH-D3, a low calcium dialysate with an ionized calcium concentration of 1.25 mM has been developed. However, it has been found that use of the low calcium dialysate has lead to higher serum PTH and phosphorus levels in patients who do not receive increased doses of oral calcium supplements and phosphate binders. When the dosages of calcium supplements and phosphate binders are increased, serum levels of phosphorus become controlled, but the incidence of hypercalcemia rises markedly. Thus, there are many problems associated with the use of current vitamin D therapies for secondary hyperparathyroidism in renal disease.
As to primary hyperparathyroidism, the current treatment is surgical, i.e., resection of the hyperplastic gland. For many patients, however, surgery is contraindicated. In such cases, medical management merely consists of following the patient without specific therapy but monitoring bone and renal function periodically to ensure that silent osseous and renal deterioration do not occur. Management of this disease would be greatly improved by the advent of effective medical modalities.
Notwithstanding these known problems with use of the hormonally active vitamin D3 for hyperparathyroidism, the art has not adequately responded with the introduction of other vitamin D compounds, derivatives or analogs that possess less inherent toxicity.
The present invention provides a method for treating or preventing hyperparathyroidism by lowering (or maintaining low) serum parathyroid hormone levels in a patient suffering from the disease. As used herein, the term xe2x80x9chyperparathyroidismxe2x80x9d refers to primary hyperparathyroidism, secondary hyperparathyroidism and hyperparathyroidism secondary to end stage renal disease. The method at the same time ameliorates bone metabolism abnormalities which can develop in such patients.
The foregoing, and other advantages of the present invention, are realized in one aspect thereof in a method for lowering serum (or plasma) PTH in patients suffering from hyperparathyroidism which comprises administering to these patients an effective amount of a vitamin D analog 1xcex1,24(S)-(OH)2-vitamin D2 to lower the serum PTH level. The analog is an active vitamin D compound which has potent biological activity but low calcemic activity relative to the active forms of vitamin D3. 1xcex1,24(S)-(OH)2-vitamin D2 may be administered in a dosage amount of about 1 to about 300 xcexcg per week.
As used herein, the term xe2x80x9cvitamin D analogxe2x80x9d is meant to refer to compounds having vitamin D hormonal bioactivity. It is also noted that a shorthand notation is often used for the D hormones, e.g., 1xcex1-hydroxy vitamin D2 may be referred to as 1xcex1-OH-vitamin D2 or simply 1xcex1-OH-D2.
In another aspect, the invention is a pharmaceutical composition having serum (or plasma) PTH lowering activity, which includes, in unit dosage form, an effective amount of 1xcex1,24(S)-(OH)2-vitamin D2 and a pharmaceutically acceptable excipient.
The treatment method of the present invention is an alternative to conventional therapy with 1xcex1,25-(OH)2 vitamin D3 or 1xcex1-OH-vitamin D3; the method is characterized by providing an active vitamin D compound having equivalent bioactivity but much lower toxicity than these conventional therapies. This is true especially in the case where oral calcium phosphate binders are used concomitantly to control serum phosphorus. As such, the method addresses a long felt need in hyperparathyroidism therapy.
Other advantages and a fuller appreciation of the invention will be gained upon an examination of the following detailed description.